Whole Thorax Irradiation of Non-human Primates Induces Persistent Nuclear Damage and Gene Expression Changes in Peripheral Blood Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2018 Jan 20

PMID 29351567

Citations 24

Authors

Shanaz A Ghandhi

Helen C Turner

Igor Shuryak

Gregory O Dugan

J Daniel Bourland

John D Olson

Janet A Tooze

Shad R Morton

Ines Batinic-Haberle

J Mark Cline

Sally A Amundson

Affiliations

Soon will be listed here.

Abstract

We investigated the cytogenetic and gene expression responses of peripheral blood cells of non-human primates (NHP, Macaca mulatta) that were whole-thorax irradiated with a single dose of 10 Gy. In this model, partial irradiation of NHPs in the thoracic region (Whole Thorax Lung Irradiation, WTLI) allows the study of late radiation-induced lung injury, while avoiding acute radiation syndromes related to hematopoietic and gastrointestinal injury. A transient drop in circulating lymphocytes and platelets was seen by 9 days, followed by elevations in respiratory rate, circulating neutrophils, lymphocytes, and monocytes at 60-100 days, corresponding to computed tomography (CT) and histologic evidence of pneumonitis, and elective euthanasia of four animals. To evaluate long-term DNA damage in NHP peripheral blood lymphocytes after 10 Gy WTLI, we used the cytokinesis-block micronucleus (CBMN) assay to measure chromosomal aberrations as post-mitotic micronuclei in blood samples collected up to 8 months after irradiation. Regression analysis showed significant induction of micronuclei in NHP blood cells that persisted with a gradual decline over the 8-month study period, suggesting long-term DNA damage in blood lymphocytes after WTLI. We also report transcriptomic changes in blood up to 30 days after WTLI. We isolated total RNA from peripheral blood at 3 days before and then at 2, 5 and 30 days after irradiation. We identified 1187 transcripts that were significantly changed across the 30-day time course. From changes in gene expression, we identified biological processes related to immune responses, which persisted across the 30-day study. Response to oxygen-containing compounds and bacteria were implicated by gene-expression changes at the earliest day 2 and latest, day 30 time-points. Gene expression changes suggest a persistent altered state of the immune system, specifically response to infection, for at least a month after WTLI.

Citing Articles

Whole-blood RNA biomarkers for predicting survival in non-human primates following thoracic radiation.

Aryankalayil M, Patel H, May J, Shankavaram U, Bylicky M, Martello S Sci Rep. 2024; 14(1):22957.

PMID: 39362942 PMC: 11449919. DOI: 10.1038/s41598-024-72975-y.

Longitudinal multi-omic changes in the transcriptome and proteome of peripheral blood cells after a 4 Gy total body radiation dose to Rhesus macaques.

Ghandhi S, Morton S, Shuryak I, Lee Y, Soni R, Perrier J BMC Genomics. 2023; 24(1):139.

PMID: 36944971 PMC: 10031949. DOI: 10.1186/s12864-023-09230-7.

Quantitative Assessment and Comparative Analysis of Longitudinal Lung CT Scans of Chest-Irradiated Nonhuman Primates.

Thakur P, Olson J, Dugan G, Bourland J, Kock N, Cline J Radiat Res. 2022; 199(1):39-47.

PMID: 36394559 PMC: 9987082. DOI: 10.1667/RADE-21-00225.1.

A Review of Radiation-Induced Alterations of Multi-Omic Profiles, Radiation Injury Biomarkers, and Countermeasures.

Shakyawar S, Mishra N, Vellichirammal N, Cary L, Helikar T, Powers R Radiat Res. 2022; 199(1):89-111.

PMID: 36368026 PMC: 10279411. DOI: 10.1667/RADE-21-00187.1.

Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation.

Vellichirammal N, Sethi S, Pandey S, Singh J, Wise S, Carpenter A Mol Ther Nucleic Acids. 2022; 29:584-598.

PMID: 36090752 PMC: 9418744. DOI: 10.1016/j.omtn.2022.08.006.

References

Thierens H, De Ruyck K, Vral A, de Gelder V, Whitehouse C, Tawn E . Cytogenetic biodosimetry of an accidental exposure of a radiological worker using multiple assays. Radiat Prot Dosimetry. 2005; 113(4):408-14. DOI: 10.1093/rpd/nch483. View

Dressman H, Muramoto G, Chao N, Meadows S, Marshall D, Ginsburg G . Gene expression signatures that predict radiation exposure in mice and humans. PLoS Med. 2007; 4(4):e106. PMC: 1845155. DOI: 10.1371/journal.pmed.0040106. View

Prado C, Kazi A, Bennett A, MacVittie T, Prado K . Mean Organ Doses Resulting From Non-Human Primate Whole Thorax Lung Irradiation Prescribed to Mid-Line Tissue. Health Phys. 2015; 109(5):367-73. PMC: 4593315. DOI: 10.1097/HP.0000000000000336. View

Daadi M, Barberi T, Shi Q, Lanford R . Nonhuman primate models in translational regenerative medicine. Stem Cells Dev. 2014; 23 Suppl 1:83-7. PMC: 4236035. DOI: 10.1089/scd.2014.0374. View

MacVittie T . The MCART Consortium animal models series. Health Phys. 2012; 103(4):340-2. DOI: 10.1097/HP.0b013e318261175a. View

Port M, Herodin F, Valente M, Drouet M, Ullmann R, Majewski M . Pre-Exposure Gene Expression in Baboons with and without Pancytopenia after Radiation Exposure. Int J Mol Sci. 2017; 18(3). PMC: 5372557. DOI: 10.3390/ijms18030541. View

Gundemir S, Colak G, Tucholski J, Johnson G . Transglutaminase 2: a molecular Swiss army knife. Biochim Biophys Acta. 2011; 1823(2):406-19. PMC: 3265640. DOI: 10.1016/j.bbamcr.2011.09.012. View

Acharya S, Fendler W, Watson J, Hamilton A, Pan Y, Gaudiano E . Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury. Sci Transl Med. 2015; 7(287):287ra69. PMC: 4686271. DOI: 10.1126/scitranslmed.aaa6593. View

Petibone D, Morris S, Hotchkiss C, Mattison D, Tucker J . Technique for culturing Macaca mulatta peripheral blood lymphocytes for fluorescence in situ hybridization of whole chromosome paints. Mutat Res. 2008; 653(1-2):76-81. DOI: 10.1016/j.mrgentox.2008.03.012. View

10.

Fenech M, Morley A . Measurement of micronuclei in lymphocytes. Mutat Res. 1985; 147(1-2):29-36. DOI: 10.1016/0165-1161(85)90015-9. View

11.

Meadows S, Dressman H, Muramoto G, Himburg H, Salter A, Wei Z . Gene expression signatures of radiation response are specific, durable and accurate in mice and humans. PLoS One. 2008; 3(4):e1912. PMC: 2271127. DOI: 10.1371/journal.pone.0001912. View

12.

Fenech M, Chang W, Kirsch-Volders M, Holland N, Bonassi S, Zeiger E . HUMN project: detailed description of the scoring criteria for the cytokinesis-block micronucleus assay using isolated human lymphocyte cultures. Mutat Res. 2002; 534(1-2):65-75. DOI: 10.1016/s1383-5718(02)00249-8. View

13.

Leinonen H, Kansanen E, Polonen P, Heinaniemi M, Levonen A . Dysregulation of the Keap1-Nrf2 pathway in cancer. Biochem Soc Trans. 2015; 43(4):645-9. DOI: 10.1042/BST20150048. View

14.

Boraschi D, Tagliabue A . The interleukin-1 receptor family. Semin Immunol. 2013; 25(6):394-407. DOI: 10.1016/j.smim.2013.10.023. View

15.

Kim W, Oh S, Woo J, Hong W, Lee H . Targeting heat shock protein 90 overrides the resistance of lung cancer cells by blocking radiation-induced stabilization of hypoxia-inducible factor-1alpha. Cancer Res. 2009; 69(4):1624-32. PMC: 2646382. DOI: 10.1158/0008-5472.CAN-08-0505. View

16.

Iskow R, Gokcumen O, Abyzov A, Malukiewicz J, Zhu Q, Sukumar A . Regulatory element copy number differences shape primate expression profiles. Proc Natl Acad Sci U S A. 2012; 109(31):12656-61. PMC: 3411951. DOI: 10.1073/pnas.1205199109. View

17.

Mehta K, Kumar A, Kim H . Transglutaminase 2: a multi-tasking protein in the complex circuitry of inflammation and cancer. Biochem Pharmacol. 2010; 80(12):1921-9. DOI: 10.1016/j.bcp.2010.06.029. View

18.

Schmittgen T, Livak K . Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008; 3(6):1101-8. DOI: 10.1038/nprot.2008.73. View

19.

Dillman 3rd J, Phillips C . Comparison of non-human primate and human whole blood tissue gene expression profiles. Toxicol Sci. 2005; 87(1):306-14. DOI: 10.1093/toxsci/kfi243. View

20.

Butturini A, de Souza P, Gale R, Cordiero J, Lopes D, Neto C . Use of recombinant granulocyte-macrophage colony stimulating factor in the Brazil radiation accident. Lancet. 1988; 2(8609):471-5. DOI: 10.1016/s0140-6736(88)90121-3. View